Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts

Abstract

The Wnt signaling pathway is crucial for osteogenesis and regulates terminal osteoblast differentiation. Although osteoarthritic (OA) osteoblasts show an abnormal phenotype and poor in vitro mineralization, the mechanism leading to this situation still remains unknow. Recent evidence indicates that Wnt signaling may be altered in OA osteoblasts. In this study we determined whether an alteration of the Wnt/b-catenin signaling pathway is responsible for the abnormal phenotype of OA osteoblasts. Expression of the Wnt signaling antagonist Dickkopf-1 (DKK1) was similar in normal and OA osteoblasts, whereas DKK2 expression was higher in OA osteoblasts than in normal osteoblasts. OA osteoblasts showed a decrease of Wnt3a-dependent Wnt/b-catenin signaling, measured by the TOPflash reporter assay and by Western blot analysis, compared with normal osteoblasts. Correcting DKK2 levels in OA osteoblasts by siRNA techniques enhanced Wnt/b-catenin signaling. Elevated DKK2 levels could be explained by elevated transforming growth factor b1 (TGF-b1) in OA osteoblasts, and exogenous TGF-b1 increased DKK2 expression in normal osteoblasts, whereas ablating TGF-b1 expression in OA osteoblasts reduced DKK2 expression. Inhibiting TGF-b1 or DKK2 expression corrected the abnormal phenotype of OA osteoblasts. In vitro mineralization of OA osteoblasts also was increased by DKK2 siRNA. We conclude that elevated TGF-b1 levels in OA osteoblasts can stimulate DKK2 expression, which, in turn, is responsible, at least in part, for their abnormal phenotype. ß

Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

“…Among members of the Dkk family, Dkk-1 is known to inhibit the canonical Wnt pathway, whereas Dkk-2 inhibition of this pathway depends on cellular context (11). For instance, Dkk-2 blocks the Wnt-1-dependent canonical pathway in OA osteoblasts (12), while it is also known to activate ␤-catenin signaling in Xenopus embryos (13). These opposing effects of Dkk-2 appear to be modulated by kremen 2, which converts Dkk-2 from an agonist to an antagonist of LRP-6 (14).…”

Pathogenesis of Osteoarthritis and Substantiation of the Use of Strontium Ranelate

“…Еще одним следствием этого процесса является из-менение фенотипа и нарушение функции остеобластов и остеокластов СХК [32,33], которые продуцируют различ-ные цитокины, факторы роста, ПГ и ЛТ, инициирующие деградацию суставного хряща [34,35]. Усиление локально-го синтеза ИЛ1, ИЛ6, ФНО и ИЛ17 также способствует ус-корению остеокластогенеза и костной резорбции [36,37].…”

Osteoarthritis: rationale for a new paradigm shift involving transforming growth factor-β1

“…Early observations of OA bone tissue samples reported increased levels of TGF-β1 and IGF-1 even in non-weight-bearing joints, implying that OA could be a bone disease. Moreover, TGF-β1 levels remain elevated in isolated bone explants and in vitro osteoblasts of OA patients 41,44 . A recent study indicated that targeted overexpression of TGF-β1 in mouse osteoblasts, but not in other joint tissues, lead to OA-like features, whereas inhibition of TGF-β1 activity in subchondral bone prevented the degeneration of articular cartilage in these mice 64 .…”